Cardiac Valvulopathy Associated with Exposure to Fenfluramine or
Dexfenfluramine: U.S. Department of Health and Human Services
Interim Public Health Recommendations, November 1997

Fenfluramine and dexfenfluramine are appetite suppressants
that were in widespread use in the United States. On July 8, 1997,
24 cases of valvular heart disease in women who had been treated
with fenfluramine and phentermine were publicly reported (1).
Although valvular lesions were observed on both sides of the heart,
a left-sided valve was affected in all cases. The histopathologic
features were similar to those observed in carcinoid-induced
valvular disease, a serotonin-related syndrome. Based on these
data, the Food and Drug Administration (FDA) issued a public health
advisory on July 8, followed by letters from FDA to 700,000 U.S.
health-care practitioners and institutions requesting information
about any additional similar patients (2). Subsequently, reports of
fenfluramine- or dexfenfluramine-associated valvulopathy increased.
This report summarizes the data used by FDA in its decision to
request voluntary withdrawal of these drugs from the market and
presents interim public health recommendations for persons exposed
to these drugs.

As of September 30, FDA had received 144 individual,
provider-initiated (i.e., "spontaneous") reports involving
fenfluramine or dexfenfluramine, with or without phentermine, in
association with valvulopathy (this total included the 24 publicly
reported cases {1}). Minimal degrees of regurgitation (i.e., trace
or mild mitral regurgitation {MR} or trace aortic regurgitation
{AR}) are relatively common in the general population and are not
generally considered abnormal. Therefore, in this analysis, a case
of fenfluramine- or dexfenfluramine-associated cardiac valvulopathy
was defined as documented AR of mild or greater severity and/or MR
of moderate or greater severity after exposure to these drugs.
Of the 132 spontaneous reports with complete information, 113 (86%)
met the case definition. Of these 113 cases, 111 (98%) occurred
among women; the median age of case-patients was 44 years (range:
22-68 years). Of these 113 cases, two (2%) used fenfluramine alone;
16 (14%), dexfenfluramine alone; 89 (79%), a combination of
fenfluramine and phentermine; and six (5%), a combination of all
three drugs. None of the cases used phentermine alone. The median
duration of drug use was 9 months (range: 1-39 months). Overall, 87
(77%) of the 113 cases were symptomatic. A total of 27 (24%)
case-patients required cardiac valve-replacement surgery; of these,
three patients died after surgery.

Because symptoms frequently occur relatively late during the
course of valvular incompetence, the prevalence of valve lesions
was assessed for patients who were exposed to these drugs but who
had no obvious history of cardiac disease or cardiac symptoms. In
early September, FDA received echocardiographic reports from five
independent, unpublished echocardiographic prevalence surveys of
patients who had received dexfenfluramine or fenfluramine alone or
in combination with phentermine (Table_1). Although the
methodology
of these surveys differed, the prevalence of valvular disease
meeting the case definition was similar in all five survey
populations, ranging from 30.0% to 38.3% (overall: 32.8%; 95%
confidence interval=27.7%-38.9%) (Figure_1) (Division of
Pharmacovigilance and Epidemiology, Center for Drug Evaluation and
Research, FDA, personal communication, 1997). Where the
echocardio-graphic diagnostic classfication was intermediate, the
classification was upgraded to the higher level: for example, the
classification of mild to moderate was upgraded to moderate.
Downgrading of the diagnostic classification did not substantially
alter the prevalence of valvulopathy that met the case definition.
The duration of exposure to the drugs was determined for patients
based on the time they were treated by the centers providing the
prevalence survey data. Preliminary data suggest that the
prevalence of valvulopathy may be higher among persons exposed for
greater than or equal to 6 months: for persons with less than 3
months' exposure, the prevalence was 22% (five of 23 cases); for
persons with 3-5 months' exposure, 22% (five of 23); and for
persons with greater than or equal to 6 months' exposure, 35% (83
of 236). However, some patients may have been treated with these
drugs before visiting the centers; therefore, these patients may
have been exposed for longer durations. Of patients with
valvulopathy in these surveys, 86% had AR, and 19% had MR either
alone or in combination. An audible cardiac murmur was auscultated
in 17% of the patients meeting the case definition. The 32.8%
overall prevalence of valvular lesions meeting the case definition
in exposed persons is substantially higher than would be expected
in the general population (3). Preliminary reports from large
population-based studies of adults indicate that the prevalence of
valvular regurgitation meeting the FDA case definition is an
estimated less than or equal to 5% and may be lower among obese
persons than among nonobese persons (4; R. Devereux, New York
Hospital-Cornell Medical Center, personal communication, 1997).
However, the results of studies specifically designed to estimate
the prevalence of regurgitant valvular lesions among obese adults
who have lost weight or who have not been exposed to these drugs
have not yet been reported. Based on data from the five prevalence
surveys, FDA requested the voluntary withdrawal of fenfluramine and
dexfenfluramine from the U.S. market; on September 15, the
manufacturers and FDA announced the withdrawal of the drugs.

Editorial Note

Editorial Note: In 1959, FDA approved the prescription appetite
suppressant phentermine (Adipex{Registered}, Fastin{Registered},
and Ionamin{Registered}) for single-drug, short-term ("a few
weeks") treatment of obesity. In 1973, fenfluramine
(Pondimin{Registered}) also was approved for single-drug,
short-term use as a prescription appetite suppressant, and in 1996,
FDA approved dexfenfluramine (the dex-isomer of fenfluramine,
Redux{Registered}) as a single-drug, prescription appetite
suppressant for longer term use in markedly obese persons, noting
that safety beyond 1 year of use had not been established in
clinical trials. Both fenfluramine and dexfenfluramine appear to
act by affecting the metabolism of the neurotransmitter serotonin
in the brain. Recently, fenfluramine has been widely used both in
combination with phentermine ("fen-phen") and for periods longer
than a few weeks. Since 1995, approximately 14 million
prescriptions have been written for either fenfluramine or
dexfenfluramine; most of the product use was in women and persons
aged less than 60 years (5). Based on an assumed median treatment
course of 3-12 months and an average prescription length of 1
month, an estimated 1.2-4.7 million persons in the United States
have been exposed to these drugs.

The findings in this report indicate that a higher than
expected prevalence of cardiac valvulopathy may have occurred among
persons exposed to fenfluramine or dexfenfluramine. Factors
potentially associated with these lesions but not yet determined
are 1) the natural history of these lesions, including the relation
between the development of the lesions and duration of drug use and
whether the lesions generally resolve, progress, or remain
unchanged when the drug is discontinued; 2) the clinical importance
of mild valvulopathy in asymptomatic persons without audible
murmurs; and 3) what, if any, characteristics might predispose a
person to develop cardiac valve abnormalities during exposure to
these drugs. Based on the preliminary data indicating a higher than
expected prevalence of valvulopathy in exposed, asymptomatic
persons without murmurs, history, and physical examination alone do
not appear to be sufficiently sensitive to detect this valvulopathy
in all exposed patients, particularly in those in whom obesity
impedes auscultation of murmurs.

Patients with acquired, primarily left-sided, valvular heart
disease may be at increased risk for development of bacterial
endocarditis following certain invasive procedures. FDA is aware of
one person whose condition met the case definition and who
presented with fever and signs and symptoms of cardiac failure and,
on echocardiogram, had both AR, MR, and a large endocarditic
vegetation; blood cultures from this patient were positive for
streptococci (H. Connolly, Mayo Clinic, personal communication,
1997). Although the degree to which patients with these valvular
lesions are at risk for developing endocarditis has not yet been
determined, prudent medical management of these patients should
include appropriate antimicrobial prophylaxis before certain
invasive procedures and should be based on 1997 American Heart
Association (AHA) recommendations for preventing bacterial
endocarditis (6).

The U.S. Department of Health and Human Services (DHHS) is
issuing the following interim recommendations for persons
previously exposed to fenfluramine or dexfenfluramine. These
recommendations have been developed collaboratively by CDC, FDA,
and the National Institutes of Health (the National Heart, Lung,
and Blood Institute and the National Institute of Diabetes and
Digestive and Kidney Diseases) in consultation with the American
Heart Association, the American College of Cardiology, and the
American Dental Association and are based on data associating
exposure to these drugs (as single agents or as part of combination
therapy) with cardiac valvulopathies. As more definitive data about
the natural history of the disease become available, these DHHS
interim recommendations may be revised. To determine whether
valvulopathy is present in potentially affected persons and to
provide such persons with optimal care, DHHS recommends that:

All persons exposed to fenfluramine or dexfenfluramine, for any
period of time, either alone or in combination with other agents,
should undergo a medical history and cardiovascular examination by
their physician to determine the presence or absence of
cardiopulmonary signs or symptoms.

An echocardiographic evaluation be performed on all persons who
were exposed to fenfluramine or dexfenfluramine for any period of
time, either alone or in combination with other agents, and who
exhibit cardiopulmonary signs (including a new murmur) or symptoms
suggestive of valvular disease (e.g., dyspnea).

Although the clinical importance of asymptomatic valvular
regurgitation in exposed patients and the risk for developing
bacterial endocarditis in these patients are unknown, practitioners
should strongly consider performing echocardiography on all
persons -- regardless of whether they have cardiopulmonary signs or
symptoms -- who have been exposed to fenfluramine or
dexfenfluramine
for any period of time, either alone or in combination with other
agents, BEFORE the patient undergoes any invasive procedure for
which antimicrobial endocarditis prophylaxis is recommended by 1997
AHA guidelines. Any echocardiographic findings that meet the AHA
criteria for prophylaxis -- regardless of whether they are
attributable to possible fenfluramine or dexfenfluramine use --
should
be recognized as indications for antibiotic prophylaxis. The
invasive procedures include certain medical or dental procedures
where antibiotic prophylaxis is recommended as defined by the 1997
AHA guidelines. For emergency procedures for which cardiac
evaluation cannot be performed, empiric antibiotic prophylaxis
should be administered according to the 1997 AHA guidelines.

Because of the prevalence of minimal degrees of regurgitation in
the general population, the current case definition of
drug-associated valvulopathy should include exposed patients with
echocardiographically demonstrated AR of mild or greater severity
and/or MR of moderate or greater severity, based on published
criteria (7,8).

Optimal timing of follow-up echocardiography to determine
progression, regression, or stabilization of valvular lesions is
currently unknown. DHHS anticipates that within 1 year, sufficient
data will become available to make recommendations about the need
for continued echocardiographic monitoring. During the interim,
because patients with documented valvular disease who are at risk
for bacterial endocarditis should be offered antimicrobial
prophylaxis after their initial echocardiogram and because no other
intervention in asymptomatic patients is indicated, DHHS is not
issuing recommendations for follow-up echocardiography.
Practitioners should use their best judgment, based on the
individual patient's history, clinical presentation, and current
valvular or pulmonary hypertension status, to determine the need
for additional echocardiographic follow-up.

Health-care practitioners should continue to report to FDA
those patients with cardiac valvular lesions who have been exposed
to fenfluramine, dexfenfluramine, phentermine, or any combination
of these products. The specific information requested can be
obtained from FDA's World-Wide Web site at http://www.fda.gov/cder
(click on "What's Happening" or "Drug Information") or by calling
FDA, telephone (301) 827-3172. These reports can be sent directly
to FDA through FDA's MedWatch program (either by using the
postage-paid MedWatch form or by fax {(800) 332-0178} or can be
given over the phone {(800) 332-1088}).

DisclaimerAll MMWR HTML versions of articles are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the electronic PDF version and/or the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

**Questions or messages regarding errors in formatting should be addressed to mmwrq@cdc.gov.